Liposomal Docetaxel Research Articles

Abstract 5516: Biodistribution of liposomal docetaxel prodrug MNK-010 in mice bearing A549 human NSCLC xenografts

Abstract The anti-mitotic taxanes belong to one of the most important families of anticancer drugs that have broad anti-tumor activity and are widely used for a variety of human cancer types. However, the taxanes are limited by a number of serious pharmacological and toxicological effects. We are developing a unique delivery system for docetaxel, comprised of a PEGylated liposomal nanoparticle containing a prodrug of docetaxel to improve solubility, tolerability and increase efficacy through improved pharmacokinetics and biodistribution. In this study we evaluated the biodistribution of MNK-010, a liposomal formulation of a docetaxel prodrug in immunodeficient mice bearing A549 Human Non-Small Cell Lung Carcinoma (NSCLC) xenografts. This study tested the hypothesis that MNK-010 can produce greater plasma and tumor accumulation of docetaxel than with delivery of standard of care free docetaxel in tumor-bearing mice. Female nude mice bearing A549 human NSCLC xenografts were given a single intravenous (IV) dose of MNK-010 (40 mg/kg docetaxel molar equivalent) or free docetaxel (50 mg/kg). For each treatment group, three animals were sacrificed at various time points between 1 hr and 504 hr post injection. After euthanasia, blood, tumor, liver, kidney, spleen, lung and skeletal muscle specimens were collected. Tissue and blood samples were assayed to determine docetaxel concentrations. Administration of MNK-010 IV provided a reservoir for the continual slow release of docetaxel in the circulation and in tumors. MNK-010 increased systemic docetaxel exposure (AUC) ten-fold greater than free docetaxel injected at similar doses. MNK-010 produced sustained docetaxel levels in tumor through the 21 day observation period, resulting in four-fold greater docetaxel tumor exposure (AUC) compared to free docetaxel. The increase in MNK-010 plasma exposure as well as the enhanced permeability effect observed with liposomes likely contributed to the increased tumor exposure. In addition to improved accumulating in tumor tissue, docetaxel derived from MNK-010 also accumulated in liver, spleen and kidney. These tissues contain phagocytic cells (macrophages or mesangial) and serve as organs of elimination for chemotherapeutics. Docetaxel derived from MNK-010 was not detectable in skeletal muscle and was only found in lung over the first 24 hours post administration. In contrast, IV injection of free docetaxel produced high initial concentrations of docetaxel in all tissues evaluated, before falling quickly over time. Tumor levels decreased below levels of quantitation after nine days. This study demonstrated that Mallinckrodt Pharmaceuticals’ PEGylated liposomal docetaxel prodrug MNK-010 provided a reservoir for the continual release of docetaxel into the systemic circulation and produced an enhanced accumulation of docetaxel in A549 human NSCLC xenografts in mice compared to the standard of care docetaxel. Citation Format: Richard M. Fitch, James H. Wible, James A. Blackledge, William D. McGhee. Biodistribution of liposomal docetaxel prodrug MNK-010 in mice bearing A549 human NSCLC xenografts. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5516. doi:10.1158/1538-7445.AM2015-5516

Pharmacokinetics and tissue distribution of docetaxel liposome mediated by a novel galactosylated cholesterol derivatives synthesized by lipase-catalyzed esterification in non-aqueous phase

The purpose of this study is to synthesize a novel galactosylated cholesterol derivative, cholesterol-diethenyl decanedioate-lactitol (CHS-DD-LA) through lipase-catalyzed esterification in non-aqueous and to evaluate the preparation, pharmacokinetics and biodistribution of docetaxel (DOC) liposomes modified with CHS-DD-LA (G-DOC-L), which may actively gather at the liver compared with the conventional DOC liposomes (DOC-L) and commercial dosage form of DOC injection (DOC-i). A rapid and simple liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay was developed for the determination of the DOC concentration in plasma and tissues with Taxol as the internal standard (IS). To measure the liver-targeting effect of the G-DOC-L, relative uptake rate (Re), peak concentration ratio (Ce), targeting efficiency (Te) and relative targeting efficiency (RTe) were reduced as the evaluation parameters. The results showed that the entrapment efficiency, particle size and Zeta potential of G-DOC-L was 76.8 ± 3.5%, 95.6 nm and 27.19 mV, respectively. After i.v. administration at the dose of 2.5 mg/kg in rats, a decrease in the AUC, MRT and an increase in CL (p < 0.05) were observed in the G-DOC-L group compared with DOC-L. All these results suggested that galactose-anchored liposomes could rapidly be removed from the circulation in vivo. The tissue distribution of G-DOC-L was widely different from that of DOC-L. The Re of G-DOC-L, DOC-L on liver was 4.011, 0.102; Ce was 3.391, 0.111; Te was 55.01, 3.08, respectively, demonstrating that G-DOC-L had an excellent effect on liver-targeting, which may help to improve the therapeutic effect of hepatic diseases.

Pharmacokinetics of liver-targeted docetaxel liposomes modified with 6-O-acyl-D-galactose esters in rabbits.

The purpose of the present study was to investigate the pharmacokinetics of docetaxel liposomes modified with 6-O-acyl-D-galactose esters (Gal-DOC-L) in rabbits. A simple, rapid and sensitive high-performance liquid chromatography (HPLC) method was developed for the determination of docetaxel. Gal-DOC-L was intravenously administered to rabbits with norethisterone as the internal standard and the blood samples were collected from ear marginal veins at 0.083, 0.25, 0.5, l, 2, 4, 6, 8, 12, 16 and 24 h after treatment. The plasma concentration of docetaxel was determined by HPLC and the pharmacokinetic parameters were calculated. Docetaxel injection (DOC-I) was studied simultaneously. The results showed that the area under the curve(0-∞), t1/2α and t1/2β of Gal-DOC-L was significantly higher, while the total body clearance was lower than that of DOC-I. The results indicated that Gal-DOC-L was able to maintain a relatively high blood concentration in vivo and prolong the treatment time.

RGD-fatty alcohol-modified docetaxel liposomes improve tumor selectivity in vivo

The tripeptide arginine-glycine-aspartate (RGD) was conjugated with various fatty alcohols to obtain RGDOCnH2n+1 (n=8, 10, 12, 14, 16, 18), which were incorporated into the bilayer of docetaxel liposomes to improve their tumor specificity. The fatty alcohols were accepted as linking groups to insert the tetrapeptide RGDX (X=amino acid) into the bilayer of liposomes. RGDX was previously shown to be a potent ligand to target tumor cell-surface integrin receptors, whereas RGD was not shown to have this ability. We hypothesized that RGD-fatty alcohol conjugates lacking the fourth amine X can guide liposomes to tumors without reducing their binding affinity to integrins. Antitumor activity, pharmacokinetics and biodistribution studies were evaluated in mice inoculated with S180 sarcoma. Compared with unmodified liposomes, RGD-fatty alcohol-modified liposomes successfully delivered significantly more docetaxel to tumors, which led to significant tumor weight loss and increased tumor docetaxel concentrations accompanied by reduced liver accumulation. Improved affinity of RGD-fatty alcohols to integrins was also confirmed on A375 cell model. Further comparisons among the tumor-targeting capacities of liposomes containing RGD-fatty alcohols, RGDF-fatty alcohols and RGDV-fatty acids demonstrated that RGD-fatty alcohols were as effective as the other two tetrapeptide derivatives. Therefore, a simplified tumor-targeting delivery system using RGD-fatty alcohols was developed.

Is an Alternative Drug Delivery System Needed for Docetaxel? The Role of Controlling Epimerization in Formulations and Beyond

The presence of 7-epidocetaxel in docetaxel injection and in vivo epimerisation has been reported to be the cause for development of tumor resistance to chemotherapy including docetaxel by inducing tumor cell protein cytochrome P450 1B1. The objective of this study was to determine systemic toxicity of Taxotere® containing 10% 7-epidocetaxel and to develop PEGylated liposomal injection that could resist epimerization in vivo. Another need for PEGylated liposomal delivery of docetaxel is to avoid reported hypersensitivity reactions of marketed products like Taxotere® and Duopafei® containing high concentration of tween-80. The PEGylated liposomes loaded with docetaxel were prepared using thin film hydration method. The in vivo toxicity of Taxotere® containing 10% 7-epimer was studied in B16F10 experimental metastasis model. B16F10 experimental metastasis model using C57BL/6 mice injected with Taxotere® containing 10% 7-epimer showed higher weight loss as compared to Taxotere® containing no epimer at single dose of 40 mg/kg indicating higher systemic toxicity. Incubation of PEGylated liposomes with phosphate buffer saline (pH 7.4) containing 0.1% w/v Tween-80 for 48 h showed better resistance to docetaxel degradation when compared with Taxotere® injection indicating better in vivo stability of liposomal docetaxel. In addition, PEGylated liposomes showed enhanced in vitro cytotoxicity, against A549 and B16F10 cells, than Taxotere®. We can therefore expect less in vivo conversion of liposomal loaded docetaxel into 7-epimer, more passive targeting to tumor tissues, decreased 7-epimer induced systemic toxicity and tumor resistance to chemotherapy compared to Taxotere®. Further in vivo studies are needed to ascertain these facts.

Docetaxel-loaded liposomes: preparation, pH sensitivity, Pharmacokinetics, and tissue distribution

Docetaxel (DTX), as a member of taxoid family, has been widely used in the treatment of cancers. The present study prepared pH-sensitive DTX-loaded liposomes (DTX-Lips) by thin-film dispersion method and various physico-chemical and morphological properties were examined. The pH sensitivity of in vitro DTX release and the in vivo pharmacokinetics and tissue distribution using Kunming mice were also investigated. The mean particle size and zeta potential of DTX liposomes were (277±2) nm and (-32.60±0.26) mV, respectively. Additionally, in vitro drug release study showed that the cumulative release rate was 1.3 times more at pH 5.0 than at pH 7.4, suggesting a pH-dependent release ability of DTX-Lips. Pharmacokinetic and pharmaceutical studies in comparison with Duopafei(®) showed that the half-time period (t(1/2)) and area under the curve (AUC) of DTX-Lips in mouse plasma were 1.8 times longer and 2.6 times higher, respectively, and that DTX-Lips selectively accumulated in macrophage-rich organs such as liver and spleen. These results together suggest that the DTX-Lips could be a promising formulation for the clinical administration of DTX.

The anti-tumor performance of docetaxel liposomes surface-modified with glycyrrhetinic acid

Purpose: Anti-tumor performance of docetaxel liposomes surface-modified with glycyrrhetinic acid (GA-DX-Lip) as a new hepatocytes-targeted delivery vehicle was investigated, unmodified docetaxel liposome (DX-Lip) was chosen as a comparison.Methods: GA-DX-Lip was prepared by film dispersion method. The physicochemical properties were characterized. The cellular uptake mechanism of GA-modified liposomes was studied in hepatocytes and nonparenchymal cells. Pharmacokinetics and the anti-tumor activity in vitro and in vivo of GA-DX-Lip were investigated.Results: The size of GA-DX-Lip was about 90 nm with negative charge and the entrapment efficiency was more than 95%. GA-modified liposomes had the specific receptor-mediated cellular endocytosis to hepatocytes, and the uptake ratio of hepatocytes to nonparenchymal cells was 2.28 times. The tumor inhibitory ratio of GA-DX-Lip in vitro was 2.03 times of DX-Lip, the T/C of GA-DX-Lip was 20.14%, better than the 33.27% of DX-Lip. There was no obvious difference in pharmacokinetics parameters.Discussion and Conclusion: The preliminary cellular uptake test showed the receptor-mediated endocytosis and enhanced hepatocytes-target for GA-modified liposomes. Compared with the unmodified liposome, GA-DX-Lip possessed better anti-tumor activity and unchanged pharmacokinetic behavior. The present results suggest that the GA-modified liposomes may be a promising delivery system for hepatocytes-target.

N-octyl-O-sulfate chitosan-modified liposomes for delivery of docetaxel: Preparation, characterization, and pharmacokinetics

A N-octyl-O-sulfate chitosan (NOSC) anchored liposome system was developed as the carrier for antitumor drug, docetaxel (DTX). The physicochemical and pharmacokinetic properties of NOSC-modified DTX liposomes (NDLs) were evaluated compared with the conventional DTX liposomes (DLs) and commercial dosage form of DTX, Taxotere®. The results showed that NDLs had DTX-loading rate of 3.41%, entrapment efficiency of 61.73%, narrow distributed particle size of 147.6±1.9nm, and high zata potential of −44.2±3.9mV. The decreased permeability of the liposome bilayer was evaluated by release behavior of calcein (CAL) from the internal phase of NOSC-modified CAL liposomes (NCLs) and enhanced stability of NDLs owed to shielding effect of sulfonic shell from adsorption by BSA. After i.v. administration at the dose of 12mg/kg, a significant increase in the AUC, MRT, and T1/2β (P<0.05) was observed in NDLs group compared with DLs and Taxotere® group. AUC0–∞ of NDLs was 6.14 and 1.55 times higher than Taxotere® and DLs, respectively, and MRT0–∞ of NDLs was 5.77 and 1.37 times higher than Taxotere® and DLs, respectively. All these results suggested that anchored liposomes could increase the stability of DTX in vitro and in vivo, as compared with conventional liposomes and Taxotere®. Therefore, NOSC as a polymeric shell to liposomes was effective to enhance the stability of liposomes containing DTX.

Ovarian Tumor Targeting of Docetaxel-Loaded Liposomes Mediated by Luteinizing Hormone-Releasing Hormone Analogues

Recent studies indicate that luteinizing hormone-releasing hormone (LHRH) analogues (LHRHa), like LHRH, are able to specifically bind to LHRH receptors which are highly expressed on the extracellular membrane of ovarian tumor cells. As a targeting moiety, LHRHa can mediate the ovarian tumor targeting of docetaxel-loaded liposomes. In our study, synthesized negatively charged cholesterol succinimide (CHS) was employed for the preparation of negatively charged docetaxel-loaded liposomes, with which the positively charged LHRHa is linked via electrostatic absorption. An HPLC-based assay for determination of docetaxel (CAS 114977-28-5, Doc) in vivo and the model of ovarian cancer xenograft were established to investigat the biodistribution of docetaxel, docetaxel liposomes (Doc-Lipo), and LHRHa mediated docetaxel-loaded liposomes (LHRHa-Doc-Lipo) in nude mice. Sixty minutes after administration of LHRHa-Doc-Lipo, the concentration of docetaxel in the ovarian tumor was 2.86 times that of Doc-Lipo and 9.02 times that of Doc in the nude mice bearing ovarian tumor. LHRHa-Doc-Lipo decreased the concentration of docetaxel in the liver and spleen by 57% and 34%, respectively, as compared with Doc-Lipo. Therefore, LHRHa-Doc-Lipo exhibits potentiality as an active targeting drug delivery system for chemotherapy of ovarian tumor.

In vitro mechanistic study of cell death and in vivo performance evaluation of RGD grafted PEGylated docetaxel liposomes in breast cancer

Objectives of the investigations were to prepare RGD grafted docetaxel liposomes (RGD-PEG-LP-DC) using supercritical fluid technology and evaluate it in vitro for cytotoxicity, DNA content analysis, mechanism of cell death, and in vivo for pharmacokinetic and biodistribution studies in BALB/c mice. The RGD-PEG-LP-DCs were found to be most cytotoxic in BT-20 and MDA-MB-231 cell lines. The flowcytometry results shows at 48 hours, 96% G2 phase arrest for RGD-PEG-LP-DC at 5 nM drug concentration. The mode of cell death was found to be mainly by necrosis at low drug equivalent concentration (1 nM) and by apoptosis at high drug equivalent concentration (10 nM). With increase in time and concentration the mode of cell death by apoptosis was found to be increasing. Biodistribution demonstrated that site specific drug distribution, t1/2, and MRT improved significantly for RGD-PEG-LP-DC. From the studies site specific and sustained intracellular drug delivery from RGD-PEG-LP-DCs may provide promising strategy in enhancing embattled against breast cancer treatment. From the Clinical EditorIn this basic science study, RGD grafted PEGylated docetaxel liposomes are used as therapeutic agents in breast cancer. While this is currently at an early preclinical level, it may become a feasible approach if future studies suggest low toxicity, good bioavailability and efficacy.

Abstract A113: ATI-1123, a novel human albumin-stabilized docetaxel liposomal formulation: Final results of a phase I study in patients with advanced solid malignancies.

Abstract Background: ATI-1123 is a novel liposomal docetaxel (D) formulation utilizing human serum albumin that facilitates tumor targeting. It was hypothesized that liposomal D formulations may reduce hypersensitivity reactions, eliminate premedication requirements, have a broader therapeutic index, and enhance systemic D exposure. This study assessed the safety, tolerability, pharmacokinetics (PK) and antitumor activity of ATI-1123 in patients (pts) with advanced solid tumors. Methods: Eligible pts had progressive disease after standard therapy, measurable disease (RECIST), ECOG ≤ 2, and adequate organ function. Dosing (1 hr infusion) began at 15 mg/m2 using an accelerated titration design, followed by a modified Fibonacci schema to MTD. Dosing was continued until disease progression or unacceptable toxicities. Plasma was analyzed for encapsulated/non-encapsulated D using a validated assay. PK was determined by model independent methods. Results: 29 pts were enrolled, median age 60 yr, (range 35–81); 48% male; 6 (20.7%) NSCLC; 6 (20.7%) pancreas; 5 (17.2%) prostate; 3 (10.4%) ovary; cervix 2 (6.8%); 7 (24.2%) other. Nine out of 29 pts (31%) received prior D. Doses studied (mg/m2) were 15 (2 pts), 30 (1 pt), 60 (2 pts), 75 (8 pts), 90 (10 pts) and 110 (6 pts). MTD was 90 mg/m2. At 110 mg/m2, 2 pts experienced DLTs (Gr 3 mucositis; Gr 3 neutropenic fever) and the 90 mg/m2 cohort was expanded to 10 pts. Since 3 patients at 90 mg/m2 developed reversible, uncomplicated grade 4 neutropenia, an intermediate dose level of 75 mg/m2 was explored (8 pts) with no DLT. Five (26%) pts had hypersensitivity reactions in cycle 1, all Gr 2, managed with prolonged infusion time and/or premedication. One reaction required ATI-1123 discontinuation. No unexpected toxicities were noted compared to standard D. PR was seen in 1 NSCLC pt, and SD was noted in 22 of 29 pts (75.9%; pancreatic, 6; NSCLC, 5; prostate, 5; other, 6). Two prostate cancer pts had robust PSA response (&amp;gt;95% reduction) following multiple treatment cycles. PK results demonstrated linear and dose proportional PK. ATI-1123 appears to enhance the drug exposure compared to standard D, as demonstrated by Cmax and AUC0–24 ratios which were 1.60–3.32 and 1.80–4.11 fold higher, respectively, and by D clearance which was 1.68–4.10 fold lower with ATI-1123. Conclusions: ATI-1123 is a novel albumin-stabilized liposomal D formulation which demonstrated acceptable tolerability, a favorable PK profile and antitumor activity that warrant exploration in larger Phase 2 trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A113.

Solid dispersion and effervescent techniques used to prepare docetaxel liposomes for lung-targeted delivery system: in vitro and in vivo evaluation

A lung-targeting liposomal docetaxel was developed to improve therapeutic index and to reduce side effects. Docetaxel proliposomes composed of docetaxel/Tween-80/Phospholipon 90H/cholesterol/citric acid at molar ratio of 0.18:0.09:3.78:3.78:91.17 were prepared by solid dispersion technique, and then were hydrated with NaHCO3 solution to obtain docetaxel liposomes by effervescent technique. The stability of proliposomes containing docetaxel, characterization and evaluation of lung-targeting effect of docetaxel liposomes in rabbit were studied. Docetaxel proliposomes were stable at 6 ± 2°C for at least 12 months. The particle size, zeta-potential, and entrapment efficiency of the resulted liposomes were 1011 ± 22 nm, −23.7 ± 0.26 mv, and 90.12 ± 0.36%, respectively. As far as the targeting parameters are concerned, the relative intake rate (Re) and the ratio of peak concentration (Ce) of lung were 28.91 and 74.28, respectively. Compared with liver, spleen, and kidney, the ratios of targeting efficacy (Te)liposomes to (Te)injection of lung were increased by a factor of 3.16, 23.00, and 27.83, respectively. In conclusion, the negatively charged docetaxel liposomes with diameter of about 1 µm described in this study have favorable lung-targeting effect and are a promising lung-targeting carrier.

Preparation of PEGylated liposomes of docetaxel using supercritical fluid technology

The aims of this investigation were to develop a procedure to prepare and characterize docetaxel encapsulated PEGylated liposomes using supercritical carbon dioxide as antisolvent and optimize the process and formulation variables using response surface methodology. The process and formulation variables were optimized by “Box Behnken Design (BBD)” of response surface methodology (RSM) with temperature, pressure and CO 2 flow rate as independent variables and particle size and yield as dependent variables for process variables while the amount of hydrogenated soya phosphotidylcholine (HSPC), soya phosphotidylcholine (SPC) and cholesterol as independent variables and % entrapment efficiency as dependent variables for optimization of formulation variables. The optimized liposomal formulation was characterized for particle size, shape, morphology, crystallinity, zeta potential, % entrapment efficiency, residual solvent content and in vitro drug release. The process and formulation variables were optimized to achieve maximum drug entrapment efficiency and yield. Results for particle size, zeta potential, % entrapment efficiency and in vitro drug release of PEGylated liposomes were found to be 269.2 ± 2.8 nm, −27.2 ± 1.8 mV, 79.2 ± 4.4 %w/w and 37.5 ± 4.5% in 24 h, respectively. The liposomes were found to be small, unilamellar and spherical with smooth surface as seen in photomicrographs of scanning electron microscopy and transmission electron microscopy. Differential scanning calorimetry and X-ray diffraction results indicated a molecular dispersion of docetaxel in the liposomes. In this study, supercritical fluid technology was successfully used to prepare small, spherical and unilamellar liposomes of docetaxel with high entrapment. It was observed that supercritical fluid technique can be an excellent technique for preparation of docetaxel liposomes which otherwise is very difficult to prepare as a solvent free and stable liposomes.

Preparation, characterization and pharmacokinetics of N-palmitoyl chitosan anchored docetaxel liposomes

The objective of this work was to investigate the preparation, characterization and pharmacokinetics of N-palmitoyl chitosan anchored docetaxel liposomes. To decrease toxic effects and improve antitumour efficacy of the drug, docetaxel has been incorporated in liposomes; the formulation, stability and pharmacokinetics of plain docetaxel liposomes (PDLs), PEGylated docetaxel liposomes (PEGDLs) and N-palmitoyl chitosan anchored docetaxel liposomes (NDLs) were compared. NDL was more stable than PDL and PEGDL in-vitro, especially in the presence of serum at 37 degrees C. The concentration of docetaxel in the plasma of rats after intravenous administration of docetaxel injection, PDL, PEGDL and NDL was studied by RP-HPLC. The pharmacokinetic behaviour of docetaxel injection, PDL, PEGDL and NDL were significantly different. These findings suggest that anchored liposomes could increase the stability of docetaxel in-vivo, as compared with plain liposomes, but the improvement was not more significant than PEGylated liposomes. N-Palmitoyl chitosan as a new polymeric membrane to anchor liposome was useful to stabilize liposomes containing anti-tumour drug.

PK and tissue distribution of docetaxel in rabbits after i.v. administration of liposomal and injectable formulations

A simple and sensitive HPLC method was established and validated for the determination of docetaxel (DTX) in rabbit plasma and tissue samples. Biosamples were spiked with paclitaxel as an internal standard and pre-treated by solid phase extraction (SPE). Sample separation was performed on a reverse-phase HPLC column at 30 °C by using a mobile phase of acetonitrile–methanol–0.02 M ammonium acetate buffer (pH 5.0) (20:47.5:32.5, v/v/v) at flow rate of 1.0 mL/min The UV absorbance of the samples was measured at the wavelength of 230 nm. The standard curves were linear over the ranges of 0.02525–2.525 μg/mL for plasma, 1.010–202.00 μg/g for lung, 0.202–20.20 μg/g for spleen, liver and kidney, 0.202–10.10 μg/g for heart and stomach, 0.0505–2.02 μg/g for brain, respectively. The limits of quantification (LOQ) were 10.0 ng/mL in the plasma samples and 20.0 ng/g in the tissue samples, respectively. The analysis method was successfully applied to pharmacokinetics and tissue distribution studies of DTX liposomes and DTX injection after i.v. administration to the rabbits. The results showed that the liposome carrier led to a significant difference in pharmacokinetics and tissue distribution profile compared to the conventional DTX injection.

Preparation and In Vitro Evaluation of A Pegylated Nano-Liposomal Formulation Containing Docetaxel

An improved pegylated liposomal formulation of docetaxel has been developed with the purpose of improving the docetaxel solubility without any need to use tween80 that is responsible for hypersensitivities following administration. Liposomes all had spherical shape with size of 130–160 nm. The most important finding of this study is that pegylated liposomes were prepared with significant increase in docetaxel encapsulation efficiency and stability of the formulation in comparison with last reports on docetaxel liposomes. In vitro release studies revealed that such a formulation could be stable in the blood circulation and meet the requirements for an effective drug delivery system.

Alternative drug formulations of docetaxel: a review

The anticancer drug docetaxel (Taxotere) is formulated in the nonionic surfactant polysorbate 80 (Tween 80). Early in the clinical development of docetaxel, it became clear that docetaxel administration is associated with the occurrence of unpredictable (acute) hypersensitivity reactions and cumulative fluid retention. These side-effects have been attributed, in part, to the presence of polysorbate 80 and have consequently initiated research focused on the development of a less-toxic, better-tolerated polysorbate 80-free formulation of docetaxel. More recently, there is an increasing interest in developing a (polysorbate 80-free) docetaxel formulation that selectively targets malignant tissue, thereby increasing efficacy while decreasing the occurrence of side-effects related to wide and nonspecific body distribution. This review aims to discuss the preclinical and clinical results of pharmaceutical strategies [PEGylated (immuno)liposomal docetaxel, docetaxel-fibrinogen-coated olive oil droplets, docetaxel encapsulated nanoparticle-aptamer bioconjugates, submicronic dispersion formulation] to develop an alternative, solvent-free, delivery form for docetaxel characterized by increased efficacy and decreased toxicity.

Radiosensitivity of human colon cancer cell enhanced by immunoliposomal docetaxel

To enhance the radiosensitivity of human colon cancer cells by docetaxel. Immunoliposomal docetaxel was prepared by coupling monoclonal antibody against carcinoembryonic antigen to cyanuric chloride at the PEG terminus of liposome. LoVo adenocarcinoma cell line was treated with immunoliposomal docetaxel or/and irradiation. MTT colorimetric assay was used to estimate cytotoxicity of immunoliposomal docetaxel and radiotoxicity. Cell cycle redistribution and apoptosis were determined with flow cytometry. Survivin expression in LoVo cells was verified by immunohistochemistry. D801 morphologic analysis system was used to semi-quantify immunohistochemical staining of survivin. Cytotoxicity was induced by immunoliposomal docetaxel alone in a dose-dependent manner. Immunoli-posomal docetaxel yielded a cytotoxicity effect at a low dose of 2 nmol/L. With a single dose irradiation, the relative surviving fraction of LoVo cells showed a dose-dependent response, but there were no significant changes as radiation delivered from 4 to 8 Gy. Compared with liposomal docetaxel or single dose irradiation, strongly radiopotentiating effects of immunoliposomal docetaxel on LoVo cells were observed. A low dose of immunoliposomal docetaxel could yield sufficient radiosensitivity. Immunoliposomal docetaxel were achieved both specificity of the conjugated antibody and drug radiosensitization. Combined with radiation, immunoliposomal docetaxel significantly increased the percentage of G(2)/M cells and induced apoptosis, but significantly decreased the percentage of cells in G(2)/G(1) and S phase by comparison with liposomal docetaxel. Immunohistochemical analysis showed that the brown stained survivin was mainly in cytoplasm of LoVo cells. Semi-quantitative analysis of the survivin immunostaining showed that the expression of survivin in LoVo cells under irradiation with immunoliposomal docetaxel was significantly decreased. Immunoliposomal docetaxel is strongly effective for target radiosensitation in LoVo colon carcinoma cells, and may offer the potential to improve local radiotherapy.

Preparation, characterization, cytotoxicity and pharmacokinetics of liposomes containing docetaxel

The taxanes, paclitaxel and docetaxel, are anticancer agents used in clinical trials against ovarian carcinoma, breast, lung and head/neck cancer. Paclitaxel, very insoluble in water, is generally formulated using Cremophor EL. Docetaxel, more soluble in water, is formulated using Tween 80 and ethanol. Tween 80, albeit less toxic than Cremophor EL, may be responsible of some toxic effects. To eliminate these vehicles and improve the drug’s antitumor efficacy, taxanes have been incorporated in liposomes. We compared formulation, stability, biodistribution and pharmacokinetics of docetaxel in conventional and PEGylated liposomes. Of the several formulations examined, docetaxel-liposomes composed of ePC/PG/CHOL 9:1:2 and ePC/PG/DSPE-PEG 2000/CHOL 9:1:2:0.7 were the most effective. Both conventional and PEGylated docetaxel-liposomes were stable at 4 °C after 15 days, whereas in the presence of serum at 37 °C they were less stable. The IC 50 values of docetaxel-liposomes, evaluated on HT-29 and Igrov1 cell lines, remained very high. Pharmacokinetics and biodistribution were evaluated in Balb/c mice after i.v. injection of [ 14C]docetaxel, formulated in Tween 80 or in 3H-labeled conventional or PEGylated liposomes. The t 1/2 β, which was low for docetaxel (52.3 min), rose to 260 min for conventional docetaxel-liposomes and to 665 min for PEGylated docetaxel liposomes. Biodistribution studies confirmed the pharmacokinetics.